Lithium treatment of bipolar disordered subjects is associated with increases (toward normal) in the volume of the left ventral anterior cingulate cortex, a structure where the grey matter volume was previously shown to be abnormally reduced in bipolar disorder. Studies performed in experimental animals or humans have suggested that this brain structure plays a major role in inhibiting or regulating the autonomic and endocrine responses to threat or stress, and the emotional feelings that occur in response to internally generated sad or anxious thoughts and memories. The abnormal reduction in volume may indicate this region?s function is impaired in bipolar disorder, dysregulating emotional expression and experience. Lithium has been shown to increase the genetic expression of proteins that exert neuroprotective and neurotrophic effects, so correcting this brain abnormality may play an integral role in lithium?s mood stabilizing effect. Effects of the psychotropic medications pramipexole and lithium are currently being persued using MRI measures of regional grey matter volume. In the past year we have obtained MRI images at higher spatial resolution than has been possible in previous studies by using a 3 Tesla MRI scanner, an MRI pulse sequence optimized for tissue contrast resolution and a 40 minute long scan. These images provide exquisite anatomical detail to increase the sensitivity of the volumetric measures. We obtained these scans in 28 bipolar subjects, of whom one-half have been recently treated with lithium or divalproex, and other one-half have not. In addition, 56 healthy controls have been scanned. In the past study year it was demonstrated that both more children of depressed parents were scanned, who are themselves putatively at high genetic risk for developing a mood disorder, also have a reduction in the ventral anterior cingulate volume. In addition, the "pregenual" portion of the corpus callossum, which carries fibers from the ventral anterior cingulate, orbital cortex, and medial prefrontal cortex areas where we identified structural abnormalities in unipolar and/or bipolar depression, was also shown to be reduced in volume both in females with unipolar depression and in females with bipolar disorder. In addition, this abnormality was evident in their children and adolescent offspring who had not yet suffered from mood disorders themselves. These data collectively demonstrated that these abnormalities may be associated with abnormalities of brain development that precede illness and also may be associated with the vulnerability to developing depression.